Total syntheses of parthenolide and its analogues with macrocyclic stereocontrol

Article abstract of DOI:10.1021/jm5009456

The first total synthesis of parthenolide (1) is described. The key feature of this synthesis is the formation of a 10-membered carbocylic ring by a macrocyclic stereocontrolled Barbier reaction, followed by a photoinduced Z/E isomerization. The biological evaluation of a small library of parthenolide analogues (19, 33, and 34) disclosed a preliminary structure-activity relationship (SAR). The results revealed that the C1, C10 double bond configuration of parthenolide has little or no effect on the activity, and the C6 and C7 configurations of the lactone ring have a moderate impact on the activities against some cancer cell lines.

Full text of DOI:10.1021/jm5009456

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Article
Total Syntheses of Parthenolide and its
Analogs with Macrocyclic Stereocontrol
Jing Long, Shan-Feng Zhang, Pan-Pan Wang, Xue-Mei Zhang, Zhong-Jin Yang, Quan Zhang, and Yue Chen
J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/jm5009456 • Publication Date (Web): 07 Aug 2014
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Total Syntheses of Parthenolide and its Analogs
with Macrocyclic Stereocontrol
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Jing Long, ShanꢀFeng Zhang, PanꢀPan Wang, XueꢀMei Zhang, ZhongꢀJin Yang, Quan Zhang*
and Yue Chen*
The State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of
Chemical Science and Engineering (Tianjin), College of Pharmacy, and Tianjin Key Laboratory
of Molecular Drug Research, Nankai University, Tianjin 300071, People's Republic of China
*Correspondence author:
Tel +86 22 23508090; Fax +86 22 23508090; Eꢀmail: zhangquan612@163.com (Q.Z.);
yuechen@nankai.edu.cn (Y.C.).
ABBREVIATIONS USED
DMAPT, dimethylaminoparthenolide; SAR, structure–activity relationship; SAE, Sharpless
asymmetric epoxidation; TBDPS, tertꢀbutyldiphenylsilyl; TBAF, tetrabutylammonium fluoride;
TFA, trifluoroacetic acid; DABCO, 1,4ꢀdiazabicyclo[2.2.2]octane; THF, tetrahydrofuran; MS,
molecular sieves; DIPT, diisopropyl tartrate; TBHP, tertꢀbutyl hydroperoxide; DMF,
dimethylformamide;
DBU,
1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene;
NaHMDS,
sodium
hexamethyldisilazide; DIBALH, diisobutylaluminum hydride; TBAI, tetrabutylammonium iodide.
ABSTRACT
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The first total synthesis of parthenolide (1) is described. The key feature of this synthesis is the
formation of a 10ꢀmembered carbocylic ring by a macrocyclic stereocontrolled Barbier reaction,
followed by a photoꢀinduced Z/E isomerization. The biological evaluation of a small library of
parthenolide analogs (19, 33 and 34) disclosed a preliminary structure–activity relationship
(SAR). The results revealed that the C1, C10 double bond configuration of parthenolide has little
or no effect on the activity; and the C6 and C7 configurations of the lactone ring have a moderate
impact on the activities against some cancer cell lines.
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INTRODUCTION
Germacranolides, a type of germacrane sesquiterpene lactone, have a unique 10ꢀmembered
carbocyclic skeleton and a transꢀ or cisꢀfused γꢀlactone containing an αꢀmethylene group in many
cases. Among them, the incorporation of an epoxide ring, hydroxyl groups, or esterified hydroxyl
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groups are common (Figure 1). Germacranolides are known to possess a wide variety of
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biological and pharmacological activities. In particular, germacranolides can be processed into a
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variety of polycyclic sesquiterpene frameworks (Scheme 1). Therefore, it was envisaged that
germacranolides would provide a platform for the total synthesis of other types of sesquiterpene
lactones. However, the total syntheses of germacranolides have remained challenging as the
germacrene carbocycle core is unstable to acidic, basic, and thermal conditions (leading to
cyclized and/or rearranged, fragmented products), and germacranolides can often exist as
conformers at ambient temperature, thus making the purification and product analysis more
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difficult. To date, there are only a few reports on the total syntheses of germacranolides. The
construction of the 10ꢀmembered ring system with stereochemical control is of paramount
importance in these endeavors. Yamakawa et al. attempted to furnish the 10ꢀmembered ring
system by a Barbierꢀtype reaction. However, they obtained dilactones fused to a 20ꢀmembered
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ring unit. Recently, Baran et al. successfully furnished the 10ꢀmembered germacrane ring system
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with a cisꢀfused γꢀlactone through a unique Pdꢀcatalyzed macrocyclization.
Parthenolide (1, Figure 1), a prominent germacranolide originally purified from the shoots of
feverfew (Tanacetum parthenium), which was used by the Europeans for a variety of ornamental
and medicinal purposes for centuries, has attracted particular attention owing to its extensive
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biological activities. Most importantly, parthenolide has been demonstrated as a small molecule
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that can selectively kill cancer stem cells. Cancer stem cells have been postulated to be
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responsible for the failure of cancer treatment. Moreover, parthenolide has been shown to inhibit
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solid tumor stem cells. However, parthenolide is unstable under both acidic and basic
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conditions as well as in media containing 0.5% serum. An aminoꢀadduct of parthenolide,
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DMAPT, has advanced into clinical studies in humans. Despite this great progress, to the best
of our knowledge, the total synthesis of parthenolide has not yet been carried out, posing a barrier
to an extensive structure–activity relationship (SAR) analysis for developing more effective and
selective parthenolideꢀbased drugs.
Recently, we reported a protecting groupꢀfree semisynthesis of parthenolide from the abundant
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natural product costunolide. Herein, we report the first asymmetric total synthesis of
parthenolide, 7ꢀepiꢀparthenolide, and their 1(10)ꢀZꢀisomers. The biological evaluation of these
analogs establishing the preliminary SAR within this class of compounds is also described
RESULTS AND DISCUSSION
Compounds syntheses
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Our initial retroꢀsynthetic analysis of parthenolide is shown in Scheme 2. We envisioned that
parthenolide could be generated by lactonization from A, αꢀmethyleneꢀγꢀhydroxyl ester or αꢀ
methyleneꢀγꢀhydroxyl nitrile, which could be prepared by an intramolecular Barbierꢀtype reaction
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of B. The Barbierꢀtype reaction has been used in the total synthesis of guaianolides. The
absolute stereochemistry could be controlled by the 4(5)ꢀepoxy moiety obtained from C by a
standard Sharpless asymmetric epoxidation (SAE). Furthermore, C could be elaborated from
known compound 13.
Our investigation commenced with known compound 13 (Scheme 3), which was obtained
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from farnesol in three steps.
Treatment of 13 with methyl acrylate and 1,4ꢀ
diazabicyclo[2.2.2]octane (DABCO) gave substituted acrylate 14, which then was chlorinated
with simultaneous double bond isomerization to afford (Z)ꢀ15 exclusively. However, cleavage of
the TBDPS protecting group of 15 was unexpectedly difficult. Under standard TBAF or TFA
conditions, no desired alcohol 16 was detected, and the starting material decomposed to a
complex mixture. Fortunately, TBDPS deprotection of 15 was achieved using HFꢀpyridine in
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1% yield. The formed primary alcohol 16 was subjected to the standard SAE reaction to
produce compound 17, which underwent oxidation to yield the corresponding aldehyde 18. At
this juncture, we poised to investigate the cyclization of 18 to construct the desired 10ꢀmembered
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ring. Under a variety of reductive Barbierꢀtype coupling conditions, Zn , In , SmI , or
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CrCl2 in THF, no desired product was detected. Interestingly, this cyclization proceeded well
with CrCl in degassed dry DMF. Without purification, the initially formed αꢀmethyleneꢀγꢀ
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hydroxyl ester intermediate was treated with DBU to generate lactone 19. However, an Xꢀray
crystal structure of the product revealed that lactone 19 was the Cꢀ7 epimer of parthenolide
(Scheme 3).
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It was hypothesized that the Zꢀallylmetal reagent led to the syn product in accordance with the
FelkinꢀAnh transition state; the relative stereochemistry of the lactone ring could be predicted
from the precedent cyclic transition state for the addition of an allylmetal reagent to aldehydes, in
which the (E)/(Z) stereochemistry of the double bond correlates to the anti/syn stereochemistry of
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the adduct. Since the Zꢀdouble bond of our allymetal substrate led to the cis adduct, we
presumed that the Eꢀdouble bond of our allymetal substrate might result in the formation of the
desired trans adduct; therefore, we designed the Eꢀallylmetal substrate from the same
intermediate 13. Similar to the above steps, the BaylisꢀHillman reaction of 13 with acrylonitrile,
followed by chlorination delivered compounds 21a and 21b in a ratio of 3:1; the major product
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1a was the Eꢀallylic chloride (Scheme 4). Compounds 21a and 21b were subjected to
deprotection, SAE, and oxidation to afford aldehydes 22a and 22b, respectively. To our surprise,
the separated aldehyde 22a or 22b went through the Barbier reaction to afford 6,7ꢀcisꢀγꢀhydroxyl
nitrile 23 exclusively, and no desired 6,7ꢀtrans product was observed. In the transformation of 23
to lactone 19, various procedures were tested, including the treatment of 23 with NaHMDS to
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remove the hydroxyl proton and lactonization, DIBALH reduction to the hemiacetal and
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reoxidation, baseꢀcatalyzed hydrolysis followed by acidic workup, as well as strong acidꢀ
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catalyzed hydrolysis with heating. However, all of these methods led to decomposition of the
starting material. The fragile epoxy moiety in 23 might be responsible for the failure of the
transformation under these conditions. Fortunately, lactone 19 was successfully synthesized by
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first transforming 23 to hydroxyl amide 24 by H O ꢀpromoted hydrolysis, followed by
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refluxing with DBU in benzene.
Both the Eꢀ and Zꢀallylmetal substrates afforded the cis adduct. Thus, the geometry of the
allylic chloride double bond was not the main factor that controlled the stereochemistry of the
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lactone ring. The failure of this approach necessitated exploration of an alternative route to
produce the desired transꢀfused lactone. The conformation or geometrical preference of the large
ring could direct the outcome of the reaction, with remote stereogenic elements providing enough
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conformational influence to direct formation of the desired product. We speculated that the
1,10ꢀdouble bond geometric configuration might affect the configuration of the two new
stereogenic centers.
First, 1(10)ꢀZꢀcyclization precursors 28a and 28b were designed and synthesized (Scheme 5).
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We commenced with the known compound 25, which was prepared from nerol in five steps.
Alcohol 25 was protected with TBDPS, and then selective cleavage of the C10ꢀC11 double bond
afforded aldehyde 26. Next, aldehyde 26 underwent the BaylisꢀHillman reaction with
acrylonitrile, followed by chlorination to generate 27a and 27b (27a:27b = 3:1). The cyclization
precursors 28a and 28b were obtained from 27a and 27b via three steps in 81% and 76% yields,
respectively.
With 28a in hand, various cyclization conditions were explored to furnish the desired 6,7ꢀtrans
30 (Table 1). Similar to our previous attempts, treatment of 28a with the common Barbierꢀtype
coupling conditions of CrCl in THF (entry 1, Table 1) did not provide any of the desired
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cyclized product. Gratifyingly, in the polar aprotic solvent DMF, compound 28a was converted
to 6,7ꢀcis 29 and the desired 6,7ꢀtrans 30 in a ratio of 1.3:1 and 35% yield (entry 2, Table 1).
Encouraged by this preliminary result, we further investigated a variety of reaction temperatures,
additives, and solvents for the cyclization induced by CrCl (entries 3–8, Table 1). However, in
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these experiments, the desired 6,7ꢀtrans 30 was obtained only as the minor product. Recently,
Baran and coworkers successfully synthesized the mediumꢀsized germacrane ring system through
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an umpolung allylation. Using their optimized conditions (entry 9, Table 1), compound 28a
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was smoothly transformed to 29 and 30 in a ratio of 2.8:1 in 16% yield (entry 9, Table 1).
Switching the catalyst from [Pd(PPh ) Cl ] to [Pd(PPh ) ] further reduced the amount of 6,7ꢀ
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trans 30 (cis:trans = 3.7:1, entry 10, Table 1). Despite extensively investigating various reaction
conditions, the Barbier reaction was met with limited success; none of the reactions proceeded
with acceptable yield or selectivity. Considering the relatively low reactivity of allylic chloride,
we added tetrabutylammonium Iodide (TBAI) to the reaction mixture, which enhanced the ratio
of 6,7ꢀtrans 30 (entry 11, Table 1). Inspired by this result, we first converted the allylic chloride
into allylic iodide and then the crude product was submitted to the Barbier reaction using CrCl2
in THF, the twoꢀsteps procedure resulted in an increased ratio of 6,7ꢀtrans 30 (1:1) and a
moderate yield (52%) (entry 12, Table 1). However, the mixed solvent of DMF/THF (1:2)
reduced the yield and ratio of 6,7ꢀtrans 30 (entry 13, Table 1).
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Following the previously optimized reaction conditions, cyclization of compound 28b afforded
a mixture of compounds 29 and 30 in a ratio of 1.9:1. This result further illustrated that the
geometry of the allylic chloride double bond was not the only important factor that controlled the
stereochemistry of the lactone ring and that the 1,10ꢀdouble bond geometric configuration also
affected the outcome of the two new stereogenic centers.
The mixture of 29 and 30 was hydrolyzed using basic hydrogen peroxide to produce
compounds 31, 32, and 33 (Scheme 6). Compound 31 was converted to lactone 34 by refluxing
in benzene with DBU. Compound 32 was unstable, and purification by silica gel column
chromatography resulted in its partial transformation into compound 33. Upon stirring with DBU
in CH Cl , complete conversion of 32 into 33 was achieved.
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With 33 in hand, completion of the synthesis entailed conversion of the 1(10)ꢀZꢀdouble bond
of 33 into the requisite E configuration (Scheme 6). Irradiation of 33 with UV light (254 nm)
afforded 1 in 58% conversion and 77% yield based on the recovery of starting material. All
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spectroscopic data of this product corresponded with the reported data for the natural product.
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Meanwhile, 1(10)ꢀEꢀ19 was irradiated to provide the corresponding product 1(10)ꢀZꢀ34 in 59%
yield based on the recovery of starting material.
Compound 35, the 1(10)ꢀZ isomer of 17, which was prepared from 26 in five steps, was also
subjected to Barbier reaction conditions (Scheme 7). Surprisingly, exposure of 35 to CrCl in
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Activities against cultured cancer cell lines
Next, parthenolide (1) and the synthesized analogs (19, 33, and 34) were subjected to
biological assays against the cultured acute myeloid leukemia cell line HLꢀ60, rat glioma cell line
C6, and human breast cancer cell lines MCFꢀ7 and SUM159. As indicated in Table 2,
compounds 1, 19, 33, and 34 showed similar activities against HLꢀ60 cells with IC values of
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2.5 ꢁM, 2.9 ꢁM, 1.2 ꢁM, and 4.2 ꢁM, respectively. Melampomagnolide B, the allylic alcohol
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analogue of compound 33 showed high activities against primary leukemia cells. For the C6
cell line, 33 was slightly more potent than parthenolide (IC50 = 3.9 ꢁM vs. 6.6 ꢁM); and
compounds 19 (IC = 24.0 ꢁM) and 34 (IC = 41.8 ꢁM) showed reduced inhibitory activities
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compared to that of parthenolide. The activity against MCFꢀ7 cells exhibited by compound 33
(IC = 5.9 ꢁM) was comparable to that of parthenolide (IC = 6.9 ꢁM), while compounds 19
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(
IC = 17.6 ꢁM) and 34 (IC = 13.0 ꢁM) showed less potency than parthenolide and compound
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33. Surprisingly, compounds 33 and 34 showed high activity against the human breast cancer cell
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line SUM159, which has a high percentage of breast cancer stem/progenitor cells, with IC50
values of 7.7 ꢁM and 3.5 ꢁM, respectively.
Based on the above activity results, the preliminary SAR was determined to be as follows: (1)
the C1, C10 double bond configuration of parthenolide has little or no effect on the activity; and
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(
2) the C6 and C7 configurations of the lactone ring have a moderate impact on the activities
against some cancer cell lines.
CONCLUSIONS
In summary, the intramolecular Barbier reaction with compounds 18, 22, 35 readily afforded
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,7ꢀcis diastereoisomer 19 as the only cyclic product. This indicate that both E and Z double
bond geometry in the allylmetal moieties correlates to the anti stereochemistry of the adduct, and
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the commonly used cyclic FelkinꢀAnh transition state is not able to explain this phenomena.
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Based upon the concept of macrocyclic stereocontrol proposed by Still, several designs and
attempts were applied to furnish the transꢀfused 10ꢀmembered germacrane ring system. The
successful final fusion started with compound 28a, and the Barbier reaction with macrocyclic
stereocontrol generated trans isomer 30 in low selectivity, followed by formation of lactone ring
to obtain compound 33, and the final photoꢀinduced Z/E double bond isomerization provided
parthenolide. Moreover, the synthetic sequences outlined in this study also enabled the formation
of some parthenolide analogs. Therefore, the synthetic route may be useful to design and
synthesize other backboneꢀmodified parthenolide analogs, so that more effective and selective
parthenolideꢀbased drugs can be developed. Finally, the syntheses to parthenolide and its analogs
illustrated here may provide a general strategy to obtain some transꢀgermacroanolide of medical
interest.
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EXPERIMENTAL SECTION
Chemistry. General. Unless otherwise mentioned, all reactions were carried out under a
nitrogen atmosphere with dry solvents under anhydrous conditions. The used solvents were
purified and dried according to common procedures (Purification of laboratory chemicals (Six
edition), Wilfred L. F. Armarego and Christina L. L. Chai). Yields refer to chromatographically
0
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and spectroscopically ( H NMR) homogeneous materials, unless otherwise stated. Reactions
were monitored by thinꢀlayer chromatography carried out on 0.25 mm Tsingdao silica gel plates
(60Fꢀ254). Visualization was achieved using UV light, phosphomolybdic acid in ethanol or
potassium permanganate in water, each followed by heating. Tsingdao silica gel (60, particle size
0.040–0.063 mm) was used for flash column chromatography. Reagents were purchased at the
highest commercial quality and used without further purification, unless otherwise stated. FTIR
spectra were obtained with a Bruker Tensor 27 instrument. All IR samples were prepared as thin
ꢀ1
1
film and reported in wave numbers (cm ). NMR spectra were recorded with a 400 MHz ( H: 400
1
3
MHz, C: 100 MHz) spectrometer and referenced to the solvent peak for CDCl . Data are
3
reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
br. = broad, m = multiplet), coupling constants and integration. The purity of the final
compounds was determined to be ≥ 95% by means of analytical high pressure liquid
chromatography (HPLC) on a Shimadzu LDꢀ20A system with an ODSꢀC18 column (4.6 × 150
mm, 5 ꢁm) eluted at 1 mL/min with MilliꢀQ water and CH CN.
3
tertꢀButyl(((2E,6E)ꢀ9ꢀ(3,3ꢀdimethyloxiranꢀ2ꢀyl)ꢀ3,7ꢀdimethylnonaꢀ2,6ꢀdienꢀ1ꢀ
yl)oxy)diphenylsilane (S1). TBDPSCl (29.1 mL, 0.124 mol) was added to a mixture of farnesol
(25.4 g, 0.115 mol), anhydrous dichloromethane (200 mL) and imidazole (9.3 g, 0.136 mol) at 0
o
C. The resulting mixture was stirred for 1 h, and then it was diluted with dichloromethane,
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poured over water, and extracted with more dichloromethane. The combined organic layer was
dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The
crude residue was dissolved in a 1.2 L solvent system of THF/H O = 3/1, was added Nꢀ
2
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60
o
bromosuccinimide (20.6 g, 0.116 mol) in small portions over a period of 1 h at 0 C. After
another 1 h stirring, 2.5 L of ether were added and the organic layer was washed with brine. The
organic layer was dried over anhydrous MgSO , and then concentrated under reduced pressure to
4
afford the crude bromohydrin. The crude bromohydrin was dissolved in a slurry containing
K CO (27.0 g, 0.207 mol) in 610 mL of methanol. After 1 h, most of the methanol was removed
2
3
under reduced pressure and the residue was extracted with diethyl ether to afford the crude
epoxides. Purification by flash column chromatography (0–1% ethyl acetate/hexane ) to provide
1
S1 (26.3 g, 0.055 mol, 48%) as a colorless oil. H NMR (400 MHz, CDCl ) δ 7.75–7.67 (m, 4H),
3
7
.45–7.35 (m, 6H), 5.39 (t, J = 6.1 Hz, 1H), 5.17 (t, J = 6.4 Hz, 1H), 4.23 (d, J = 6.2 Hz, 2H),
.71 (t, J= 6.2 Hz, 1H), 2.21–2.04 (m, 4H), 2.04–1.96 (m, 2H), 1.63 (s, 3H), 1.69–1.56 (m, 2H),
2
1
3
1.45 (s, 3H), 1.31 (s, 3H), 1.26 (s, 3H), 1.05 (s, 9H); C NMR (100 MHz, CDCl ) δ 137.1, 135.7,
3
1
34.4, 134.2, 129.6, 127.7, 124.8, 124.3, 64.3, 61.3, 58.4, 39.6, 36.5, 27.6, 27.0, 26.5, 25.0, 19.3,
8.9, 16.5, 16.2.
1
(4E,8E)ꢀ10ꢀ((tertꢀButyldiphenylsilyl)oxy)ꢀ4,8ꢀdimethyldecaꢀ4,8ꢀdienal (13). A solution of S1
(
26.1 g, 0.055 mol) in THF:H O (82:18, 365 mL) was treated with NaIO (6.68 g, 0.031 mol, 0.6
2
4
o
equiv) and HIO •2H O (13.75 g, 0.060 mol, 1.1 equiv) at 0 C. The resulting mixture was stirred
4
2
o
at 0 C for 10 min and then warmed to room temperature. After 1 h, the reaction mixture was
quenched with saturated aqueous NaHCO (250 mL), and aqueous layer was extracted with
3
EtOAc (3×500 mL). The combined organic layers were washed with brine, dried over Na SO
2
4
and concentrated under reduced pressure. The crude product was purified by silica gel column
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chromatography (0–1% ethyl acetate/hexane) to give the desired aldehyde 13 (22.5 g, 0.052 mol,
1
9
4
2
4%) as a colorless oil. H NMR (400 MHz, CDCl ): δ 9.73 (t, J = 1.2 Hz, 1H), 7.69–7.71 (m,
3
H), 7.36–7.44 (m, 6H), 5.38 (t, J = 6 Hz, 1H), 5.14 (t, J = 6.4 Hz, 1H), 4.22 (d, J = 6 Hz, 2H),
.50 (td, J = 6, 1.2 Hz, 2H), 2.31 (t, J = 7.6 Hz, 2H), 2.05–2.11 (m, 2H), 1.96–2.00 (m, 2H), 1.62
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9
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2
3
4
5
6
7
8
9
0
1
3
(
s, 3H), 1.44 (s, 3H), 1.05 (s, 9H); C NMR (100 MHz, CDCl ): δ 202.7, 136.9, 135.8, 134.2,
3
133.3, 129.7, 127.7, 125.2, 124.4, 61.3, 42.3, 39.4, 31.9, 27.0, 26.3, 19.3, 16.5, 16.3; HRMS
+
(
ESIꢀTOF) calcd for C H NaO Si [M+Na ] 457.2533, found 457.2533.
2
8
38
2
(6E,10E)ꢀMethyl
12ꢀ((tertꢀbutyldiphenylsilyl)oxy)ꢀ3ꢀhydroxyꢀ6,10ꢀdimethylꢀ2ꢀ
methylenedodecaꢀ6,10ꢀdienoate (14). A solution of aldehyde 13 (650 mg, 1.49 mmol) and
DABCO (33 mg, 0.298 mmol) in methyl acrylate (1.34 mL, 14.9 mmol) was stirred at room
temperature for 2 days, then additional DABCO (33 mg, 0.298 mmol) was added and the mixture
was stirred at room temperature for another 30 days. Evaporation in vacuum and column
chromatography (0–10% ethyl acetate/hexane) gave the hydroxyl ester 14 as a colorless oil (598
1
mg, 1.150 mmol, 77%). H NMR (400 MHz, CDCl ): δ 7.69 (d, J = 7.0 Hz, 4H), 7.47–7.32 (m,
3
6
H), 6.23 (s, 1H), 5.81 (s, 1H), 5.38 (t, J = 6.0 Hz, 1H), 5.17 (t, J = 6.4 Hz, 1H), 4.44–4.34 (m,
H), 4.22 (d, J = 6.4 Hz, 2H), 3.78 (s, 3H), 2.62–2.56 (m, 1H), 2.15–2.04 (m, 3H), 2.03–1.94 (m,
1
1
3
2H), 1.82–1.63 (m, 3H), 1.62 (s, 3H), 1.44 (s, 3H), 1.04 (s, 9H); C NMR (100 MHz, CDCl ): δ
3
166.9, 142.9, 137.0, 135.7, 134.6, 134.1, 129.5, 127.6, 124.8, 124.7, 124.2, 70.8 , 61.2, 51.8, 39.5,
−
1
3
5.9, 34.5, 26.9, 26.3, 19.2, 16.3, 16.0; IR (KBr, cm ): 3440, 3051, 2937, 1714, 1630, 1435,
+
1195, 1108, 1061, 703; HRMS (ESIꢀTOF) calcd for C H NO Si [M+NH ] 538.3347, found
3
2
48
4
4
538.3342.
(2Z,6E,10E)ꢀMethyl 12ꢀ((tertꢀbutyldiphenylsilyl)oxy)ꢀ2ꢀ(chloromethyl)ꢀ6,10ꢀdimethyldodecaꢀ
2
,6,10ꢀtrienoate (15). To a solution of 14 (520 mg, 1.00 mmol ) in dry CCl (10 mL) was added
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nꢀBu P (300 mg, 1.48 mmol) at room temperature under Ar. The resulting mixture was stirred for
3
2
h, concentrated under reduced pressure and purified by column chromatography (0–1% ethyl
1
acetate/hexane) to afford 15 as a colorless oil (447 mg, 0.831mmol, 83%). H NMR (400 MHz,
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12
13
14
15
16
17
18
19
20
21
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CDCl ): δ 7.76–7.64 (m, 4H), 7.45–7.33 (m, 6H), 6.99 (t, J = 7.6 Hz, 1H), 5.39 (t, J = 6.0 Hz,
3
1H), 5.17 (t, J = 6.2 Hz, 1H), 4.32 (s, 2H), 4.23 (d, J = 6.0 Hz, 2H), 3.79 (s, 3H), 2.42 (q, J = 7.6
Hz, 2H), 2.16 (t, J = 7.6 Hz, 2H), 2.15–2.04 (m, 2H), 1.99 (t, J = 7.6 Hz, 2H), 1.63 (s, 3H), 1.45
13
(
s, 3H), 1.05 (s, 9H); C NMR (100 MHz, CDCl ): δ 166.4, 148.6, 137.0, 135.8, 134.3, 133.6,
3
129.7, 129.2, 127.8, 125.7, 124.4, 61.3, 52.3, 39.5, 38.2, 37.4, 27.6, 27.0, 26.5, 19.4, 16.5, 16.2;
−
1
IR (KBr, cm ): 3047, 2936, 1961, 1823, 1720, 1435, 1282, 1109, 1058, 703; HRMS (ESIꢀTOF)
+
calcd for C H ClNO Si [M+NH ] 556.3008, found 556.3012.
3
2
47
3
4
(2Z,6E,10E)ꢀMethyl 2ꢀ(chloromethyl)ꢀ12ꢀhydroxyꢀ6,10ꢀdimethyldodecaꢀ2,6,10ꢀtrienoate (16).
To a solution of 15 (33 mg, 0.06 mmol) in THF (1 mL) was added pyridine hydrofluoride (70%,
0.14 mL, 1.0 mmol). The reaction mixture was stirred for 2.5 h, and then diluted with
dichloromethane (10 mL). The resulting solution was washed with saturated aqueous sodium
bicarbonate solution (5 mL), and then the organic phase was dried over magnesium sulfate and
concentrated under reduced pressure and purified by column chromatography (0–30% ethyl
1
acetate/hexane) to provide product 16 as colorless oil. (15 mg, 0.050 mmol, 91%). H NMR (400
MHz, CDCl ): δ 6.95 (t, J = 7.6 Hz, 1H), 5.36 (t, J = 6.4 Hz, 1H), 5.13 (t, J = 6.5 Hz, 1H), 4.29
3
(s, 2H), 4.11 (d, J = 6.8 Hz, 2H), 3.76 (s, 3H), 2.39 (q, J = 7.2 Hz, 2H), 2.16–2.05 (m, 4H), 2.05–
1
3
1.96 (m, 2H), 1.71 (br s , 1H), 1.63 (s, 3H), 1.59 (s, 3H); C NMR (100 MHz, CDCl ): δ 166.3,
3
148.6, 139.0, 133.6, 129.0, 125.4, 123.8, 59.4, 52.2, 39.4, 38.0, 37.3, 27.3, 26.2, 16.3, 16.0; IR
−
1
(
KBr, cm ): 3354, 2926, 2858, 1718, 1646, 1440, 1286, 1197, 779; HRMS (ESIꢀTOF) calcd for
+
C H ClNaO [M+Na ] 323.1384, found 323.1385.
1
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(
2Z,6E)ꢀMethyl
2ꢀ(chloromethyl)ꢀ9ꢀ((2R,3R)ꢀ3ꢀ(hydroxymethyl)ꢀ2ꢀmethyloxiranꢀ2ꢀyl)ꢀ6ꢀ
methylnonaꢀ2,6ꢀdienoate (17). In a 10 mL roundꢀbottom flask, 4 Å molecular sieves (100 mg)
were dispersed in anhydrous CH Cl (2.8 mL). Dꢀ(–)ꢀdiisopropyl tartrate (8.6 µL, 0.04 mmol)
2
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3
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7
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9
0
o
was added to the reaction flask and the mixture was cooled to –40 C. After 10 min, Ti(OꢀiꢀPr)4
o
(
10 µL, 0.03 mmol) was added and stirred at –40 C for 15 min. After that time, TBHP (3.3 M in
o
toluene, 0.15 mL,0.49 mmol) was introduced and the mixture was stirred at –40 C for 30 min,
then compound 16 (100 mg, 0.33 mmol) was added as a solution in anhydrous CH Cl (1 mL).
2
2
o
The reaction mixture was warmed to –18 C and kept at this temperature overnight. The reaction
was quenched by addition of acetone containing 2% water (3 mL), warmed to room temperature
and stirred for 3 h. After filtering through Celite, the solvent was dried over MgSO4,
concentrated under reduced pressure. The crude mixture was purified by column chromatography
(
0–35% ethyl acetate/hexane) to provide compound 17 as a colorless oil (98 mg, 0.310 mmol,
2
0
1
9
3%, ee = 92%). [α]D = 4.0 (c = 1.0, CHCl ); H NMR (400 MHz, CDCl ): δ 6.95 (t, J = 7.6 Hz,
3
3
1H), 5.14 (t, J = 6.7 Hz, 1H), 4.30 (s, 2H), 3.79 (dd, J = 12.0, 4.4 Hz, 1H), 3.77 (s, 3H), 3.66 (dd,
J = 12.0, 6.6 Hz, 1H), 2.94 (dd, J = 6.6, 4.4 Hz, 1H), 2.40 (q, J = 7.6 Hz, 2H), 2.14 (t, J = 7.6 Hz,
1
3
2
H), 2.13–2.03 (m, 2H), 1.70–1.63 (m, 1H), 1.61 (s, 3H), 1.52–1.42 (m, 1H), 1.27 (s, 3H); C
NMR (100 MHz, CDCl ): δ 166.4, 148.5, 134.1, 129.2, 124.9, 63.1, 61.5, 61.1, 52.3, 38.4, 38.0,
3
−1
3
7.4, 27.3, 23.6, 16.9, 16.0; IR (KBr, cm ): 3427, 3055, 2938, 2865, 1718, 1490, 1440, 1221,
+
9
54; HRMS (ESIꢀTOF) calcd for C H ClNaO [M+Na ] 339.1334, found 339.1330.
1
6
25
4
(2Z,6E)ꢀMethyl 2ꢀ(chloromethyl)ꢀ9ꢀ((2R,3S)ꢀ3ꢀformylꢀ2ꢀmethyloxiranꢀ2ꢀyl)ꢀ6ꢀmethylnonaꢀ2,6ꢀ
dienoate (18). To a solution of alcohol 17 (150 mg, 0.475 mmol) in CH Cl (6.4 mL) was added
2
2
NaHCO (395 mg, 4.702 mmol) and Dess–Martin periodinane (403 mg, 0.950 mmol) at room
3
temperature. After 1 h, sat. aq. NaHCO (10 mL) was added and the reaction mixture was stirred
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at room temperature for 10 min. The CH Cl layer was separated and the aqueous layer was
2
2
extracted with CH Cl (2 × 10 mL). The CH Cl layers were combined, dried over Na SO and
2
2
2
2
2
4
concentrated under reduced pressure. The resulting residue was purified by flash chromatography
0–15% ethyl acetate/hexane) gave aldehyde 18 (136 mg, 0.433 mmol, 91%) as a clear colorless
10
11
12
13
14
15
16
17
18
19
20
21
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23
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59
60
(
2
0
1
oil. [α]D = –42.8 (c = 1.0, CHCl ); H NMR (400 MHz, CDCl ) δ 9.44 (d, J = 5.0 Hz, 1H), 6.95
3
3
(
t, J = 7.5 Hz, 1H), 5.13 (td, J = 7.2, 0.8 Hz,1H), 4.31 (s, 2H), 3.77 (s, 3H), 3.16 (d, J = 5.0 Hz,
1
H), 2.41 (q, J = 7.5 Hz, 2H), 2.23–2.05 (m, 4H), 1.76–1.66 (m, 1H), 1.62 (s, 3H), 1.61–1.52 (m,
1
3
1H), 1.43 (s, 3H); C NMR (100 MHz, CDCl ) δ 199.5, 166.1, 148.1, 134.7, 129.1, 123.9, 64.0,
3
−
1
6
3.5, 52.1, 38.1, 37.9, 37.2, 27.2, 23.3, 17.2, 16.0; IR (KBr, cm ): 2922, 2852, 2729, 1719, 1645,
+
1
441, 1282, 781; HRMS (ESIꢀTOF) calcd for C H ClO [M+H ] 315.1358, found 315.1360.
1
6
24
4
7ꢀepiꢀParthenolide (19). Under Ar, to a solution of CrCl (86 mg, 0.699 mmol) in dry DMF
2
(
10 mL) was added a solution of the aldehyde 18 (34 mg, 0.108 mmol) in 2 mL dry DMF over 2
h at room temperature. When the addition was completed, the reaction was allowed to stir for
another 2 h and quenched with water (6.0 mL). The reaction mixture was extracted with Et O,
2
the combined organic layers were combined and washed with water and brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude residue was dissolved in 4 mL of
CH Cl to which DBU (2.1 mg, 0.014 mmol) was added. After stirring for 48 h, the reaction
2
2
mixture was concentrated, purified by flash chromatography (0–10% ethyl acetate/hexane) to
o
yield compound 19 as a white solid (11 mg, 0.044 mmol, 41% over 2 steps). mp 125–126 C;
2
0
1
[α]D = 26.4 (c = 1.0, CHCl ); H NMR (400 MHz, CDCl ): δ 6.18 (s, 1H), 5.65 (s, 1H), 5.31 (s,
3
3
1
H), 4.07 (dd, J = 9.2, 5.6 Hz, 1H), 2.98–2.89 (m, 1H), 2.81 (d, J = 9.2 Hz, 1H), 2.47–2.16 (m,
1
3
4
H), 2.15–2.03 (m, 2H), 1.71 (s, 3H), 1.62–1.51 (m, 1H), 1.30 (s, 4H); C NMR (100 MHz,
−
1
CDCl ): δ 169.8, 143.2, 121.4, 80.0, 62.4, 60.8, 16.9; IR (KBr, cm ): 3056, 2930, 2867, 1753,
3
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6
+
1
599, 1491, 1440, 1226, 950; HRMS (ESIꢀTOF) calcd for C H O [M+H ] 249.1485, found
15 21 3
249.1489.
(
6E,10E)ꢀ12ꢀ((tertꢀButyldiphenylsilyl)oxy)ꢀ3ꢀhydroxyꢀ6,10ꢀdimethylꢀ2ꢀmethylenedodecaꢀ6,10ꢀ
0
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4
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7
8
9
0
1
2
3
4
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6
7
8
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7
8
9
0
dienenitrile (20). A solution of aldehyde 13 (18.9 g, 43.548 mmol) and DABCO (970 mg, 8.661
mmol) in acrylonitrile (86 mL, 1.313 mol) was stirred at room temperature for 2 days, then
additional DABCO (970 mg, 8.661 mmol) was added and the mixture was stirred at room
temperature for another 20 days. The mixture was concentrated and the residue was purified by
silica gel column chromatography (0–10% ethyl acetate/hexane) to give compound 20 (17.2 g,
1
3
5.318 mmol, 81%) as an colorless oil. H NMR (400 MHz, CDCl ) δ 7.74–7.67 (m, 4H), 7.48–
3
7
.34 (m, 6H), 5.97 (d, J = 0.8 Hz, 1H), 5.95 (s, 1H), 5.39 (t, J = 6.0 Hz, 1H), 5.20 (t, J = 6.4 Hz,
1H), 4.28–4.16 (m, 3H), 2.26 (dd, J = 9.6, 4.9 Hz, 1H), 2.16–2.07 (m, 4H), 2.02 (t, J = 7.2 Hz,
1
3
2
H), 1.91–1.81 (m, 1H), 1.78–1.70 (m, 1H), 1.65 (s, 3H), 1.46 (s, 3H), 1.07 (s, 9H); C NMR
(
100 MHz, CDCl ) δ 137.0, 135.8, 134.1, 134.0, 129.8, 129.7, 127.8, 127.1, 125.8, 124.4, 117.2,
3
−
1
71.9, 61.4, 39.4, 35.4, 33.7, 27.0, 26.2, 19.3, 16.4, 15.9; IR (KBr, cm ): 3471, 3064, 2933, 2858,
+
2
227, 1667, 1431, 1108, 1059, 703; HRMS (ESIꢀTOF) calcd for C H NO Si [M+H ] 488.2979,
3
1
42
2
found 488.2981.
(2E,6E,10E)ꢀ12ꢀ((tertꢀButyldiphenylsilyl)oxy)ꢀ2ꢀ(chloromethyl)ꢀ6,10ꢀdimethyldodecaꢀ2,6,10ꢀ
trienenitrile (21a) and (2Z,6E,10E)ꢀ12ꢀ((tertꢀbutyldiphenylsilyl)oxy)ꢀ2ꢀ(chloromethyl)ꢀ6,10ꢀ
dimethyldodecaꢀ2,6,10ꢀtrienenitrile (21b). To a solution of 20 (1.21 g, 2.485 mmol ) in dry CCl4
(24.8 mL) was added nꢀBu P (0.92 mL, 3.677 mmol) at room temperature under Ar. After 2 h,
3
the reaction mixture was concentrated and purified by column chromatography (0–1% ethyl
acetate/hexane) to provide 21a (748 mg, 1.481 mmol, 60%) and 21b (250 mg, 0.495 mmol, 20%).
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1
2
1a: H NMR (400 MHz, CDCl ) δ 7.78–7.64 (m, 4H), 7.49–7.33 (m, 6H), 6.46 (t, J = 7.6 Hz,
3
1
H), 5.40 (t, J = 5.8 Hz, 1H), 5.15 (t, J = 6.4 Hz, 1H), 4.25 (d, J = 6.2 Hz, 2H), 4.09 (s, 2H), 2.53
(
q, J = 7.4 Hz, 2H), 2.15 (t, J = 7.2 Hz, 2H), 2.12–2.06 (m, 2H),2.07–1.96 (m, 2H), 1.65 (s, 3H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
1
.46 (s, 3H), 1.07 (s, 9H); C NMR (100 MHz, CDCl ) δ 151.9, 136.9, 135.8, 134.2, 132.9,
3
1
29.7, 127.7, 126.3, 124.4, 115.7, 112.5, 61.3, 44.1, 39.4, 37.9, 29.9, 27.0, 26.4, 19.3, 16.5, 16.0;
−
1
IR (KBr, cm ): 3062, 2933, 2858, 2223, 1639, 1433, 1266, 1108, 1057, 705; HRMS (ESIꢀTOF)
+
calcd for C H ClNNaOSi [M+Na ] 528.2460, found 528.2457.
3
1
40
1
21b: H NMR (400 MHz, CDCl ) δ 7.74–7.66 (m, 4H), 7.46–7.34 (m, 6H), 6.52 (t, J = 7.6 Hz,
3
1
H), 5.39 (t, J = 6.2 Hz, 1H), 5.16 (t, J = 6.6 Hz, 1H), 4.24 (d, J = 6.2 Hz, 2H), 4.11 (s, 2H), 2.38
(
q, J = 7.5 Hz, 2H), 2.18–2.04 (m, 4H), 2.05–1.96 (m, 2H), 1.62 (s, 3H), 1.46 (s, 3H), 1.05 (s,
1
3
9H); C NMR (100 MHz, CDCl ) δ 152.6, 136.9, 135.8, 135.0, 134.3, 129.8, 127.8, 126.5,
3
−
1
1
24.5, 118.2, 112.4, 61.3, 39.4, 38.3, 37.8, 27.4, 27.0, 26.8, 19.4, 16.5, 16.1; IR (KBr, cm ):
3
048, 2932, 2857, 2224, 1963, 1667, 1634, 1590, 1427, 1109, 1058; HRMS (ESIꢀTOF) calcd for
+
C H ClN OSi [M+NH ] 523.2906, found 523.2903.
3
1
44
2
4
(
2E,6E,10E)ꢀ2ꢀ(Chloromethyl)ꢀ12ꢀhydroxyꢀ6,10ꢀdimethyldodecaꢀ2,6,10ꢀtrienenitrile (S2). To
a solution of 21a (140 mg, 0.277 mmol) in THF (5 mL) was added pyridine hydrofluoride (70%,
0.26 mL, 1.857 mmol). The reaction mixture was stirred for 2.5 h, and then diluted with
dichloromethane (40 mL). The resulting solution was washed with saturated aqueous sodium
bicarbonate solution (10 mL), then the organic phase was dried over magnesium sulfate and the
solvent was removed under reduced pressure. Resulting residue was purified by column
chromatography (0–30% ethyl acetate/hexane) to give the alcohol S2 as a colorless oil. (57 mg,
1
0
.213 mmol, 88%). H NMR (400 MHz, CDCl ) δ 6.46 (t, J = 7.6 Hz, 1H), 5.36 (t, J = 6.8 Hz,
3
1
H), 5.10 (t, J = 6.4 Hz, 1H), 4.11 (d, J = 6.7 Hz, 2H), 4.08 (s, 2H), 2.49 (q, J = 7.4 Hz, 2H),
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2
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
4
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5
5
5
5
5
5
5
6
13
2
.15–2.04 (m, 4H), 2.04–1.96 (m, 2H), 1.71 (br s, 1H), 1.63 (s, 3H), 1.59 (s, 3H); C NMR (100
MHz, CDCl ) δ 151.9, 139.0, 133.0, 125.9, 123.8, 115.6, 112.5, 59.3, 44.0, 39.3, 37.8, 29.9, 26.2,
3
–
1
1
6.3, 15.9; IR (KBr, cm ): 3351, 2921, 2860, 2224, 1666, 1638, 1441, 1270, 1000, 715; HRMS
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
(ESIꢀTOF) calcd for C H ClNNaO [M+Na ] 290.1282, found 290.1285.
1
5
22
(
2E,6E)ꢀ2ꢀ(Chloromethyl)ꢀ9ꢀ((2R,3R)ꢀ3ꢀ(hydroxymethyl)ꢀ2ꢀmethyloxiranꢀ2ꢀyl)ꢀ6ꢀmethylnonaꢀ
2
,6ꢀdienenitrile (S3). In a 10 mL roundꢀbottom flask, 4 Å molecular sieves (200 mg) were
dispersed in anhydrous CH Cl (6 mL). Dꢀ(–)ꢀdiisopropyl tartrate (18 µL, 0.087 mmol) was
2
2
o
added to the reaction flask and the mixture was cooled to –40 C. After 10 min, Ti(OꢀiꢀPr) (20
4
o
µL, 0.072 mmol) was added and stirred at –40 C for 15 min. After that time, TBHP (3.3 M in
o
toluene, 0.33 mL, 1.089 mmol) was introduced and the mixture was stirred at –40 C for 30 min,
then a solution of S2 (193 mg, 0.723 mmol) in dry CH Cl (1.5 mL) was added. The reaction
2
2
o
mixture was warmed to –18 C and kept at this temperature overnight. The reaction was
quenched by addition of acetone containing 2% water (6 mL), warmed to room temperature and
stirred for 3 h. After filtering through Celite, the solvent was dried over MgSO , concentrated
4
under reduced pressure. The crude mixture was purified by column chromatography (0–35%
ethyl acetate/hexane) to provide S3 as a colorless oil (186 mg, 0.658 mmol, 91%, ee = 88%).
2
0
1
[α]D = 8.6 (c = 1.0, CHCl ); H NMR (400 MHz, CDCl ) δ 6.47 (t, J = 7.6 Hz, 1H), 5.12 (t, J =
3
3
7
.0 Hz, 1H), 4.09 (s, 2H), 3.84–3.74 (m, 1H), 3.70–3.59 (m, 1H), 2.93 (dd, J = 6.6, 4.4 Hz, 1H),
.50 (q, J = 7.4 Hz, 2H), 2.32 (br s, 1H), 2.17–2.02 (m, 4H), 1.69–1.62 (m, 1H), 1.61 (s, 3H),
2
1
3
1.49 (ddd, J = 13.7, 9.0, 7.1 Hz, 1H), 1.27 (s, 3H); C NMR (100 MHz, CDCl ) δ 151.8, 133.4,
3
–1
1
25.4, 115.6, 112.5, 63.0, 61.4, 61.0, 44.0, 38.2, 37.7, 29.8, 23.5, 16.7, 15.9; IR (KBr, cm ):
3
428, 3055, 2934, 2863, 2224, 1637, 1441, 1222, 1031, 717; HRMS (ESIꢀTOF) calcd for
+
C H ClNO [M+H ] 284.1412, found 284.1417.
1
5
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2
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(
2E,6E)ꢀ2ꢀ(Chloromethyl)ꢀ9ꢀ((2R,3S)ꢀ3ꢀformylꢀ2ꢀmethyloxiranꢀ2ꢀyl)ꢀ6ꢀmethylnonaꢀ2,6ꢀ
dienenitrile (22a). To a solution of S3 (49 mg, 0.173 mmol) in CH Cl (2.5 mL) was added
2
2
NaHCO (145 mg, 1.726 mmol) and Dess–Martin periodinane (146 mg, 0.344 mmol) at room
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
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37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
temperature. After 1 h, sat. aq. NaHCO (5 mL) was added. The resulting mixture was stirred at
3
room temperature for 10 min. The CH Cl layer was separated and the aqueous layer was
2
2
extracted with CH Cl (2 × 5 mL). The CH Cl layers were combined, dried over Na SO and
2
2
2
2
2
4
concentrated under reduced pressure. The crude product was purified by flash chromatography
(0–15% ethyl acetate/hexane) to give 22a (44 mg, 0.157 mmol, 91%) as a clear colorless oil.
2
0
1
[
α]D = –59.4 (c = 1.0, CHCl ); H NMR (400 MHz, CDCl ) δ 9.45 (d, J = 5.0 Hz, 1H), 6.48 (t,
3 3
J = 7.6 Hz, 1H), 5.11 (t, J = 6.9 Hz, 1H), 4.10 (s, 2H), 3.16 (d, J = 4.9 Hz, 1H), 2.52 (q, J = 7.4
Hz, 2H), 2.24–2.05 (m, 4H), 1.71 (dt, J = 15.1, 7.6 Hz, 1H), 1.62 (s, 3H),1.65–1.55 (m, 1H), 1.43
1
3
(
s, 3H); C NMR (100 MHz, CDCl ) δ 199.7, 151.6, 134.1, 124.7, 115.6, 112.7, 64.1, 63.5, 44.0,
3
−
1
3
8.1, 37.8, 29.7, 23.4, 17.3, 16.0; IR (KBr, cm ): 2929, 2731, 2223, 1720, 1637, 1445, 715;
+
HRMS (ESIꢀTOF) calcd for C H ClNO [M+H ] 282.1255, found 282.1260.
1
5
21
2
(2Z,6E,10E)ꢀ2ꢀ(Chloromethyl)ꢀ12ꢀhydroxyꢀ6,10ꢀdimethyldodecaꢀ2,6,10ꢀtrienenitrile (S4). To a
solution of 21b (380 mg, 0.752 mmol) in THF (11 mL) was added Ppyridine hydrofluoride (70%,
0.67 mL, 4.785 mmol). The reaction mixture was stirred for 2.5 h, and diluted with
dichloromethane (80 mL). The resulting solution was washed with saturated aqueous sodium
bicarbonate solution (30 mL), and then the organic phase was dried over magnesium sulfate. The
solvent was removed under reduced pressure. The crude residue was purified by column
chromatography (0–30% ethyl acetate/hexane) to afford S4 (178 mg, 0.669 mmol, 89%) as a
1
colorless oil. H NMR (400 MHz, CDCl ) δ 6.52 (t, J = 7.6 Hz, 1H), 5.43–5.36 (m, 1H), 5.14 (t,
3
J = 6.4 Hz, 1H), 4.15 (d, J = 6.7 Hz, 2H), 4.12 (s, 2H), 2.39 (q, J = 7.4 Hz, 2H), 2.17–2.09 (m,
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
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5
5
5
5
5
6
13
4
H), 2.08–2.01 (m, 2H), 1.67 (s, 3H), 1.60 (s, 3H), 1.38 (br s, 1H); C NMR (100 MHz, CDCl )
3
δ 152.6, 139.1, 132.8, 126.3, 123.9, 118.2, 112.3, 59.5, 39.4, 38.3, 37.8, 27.2, 26.3, 16.4, 16.0; IR
−
1
(
KBr, cm ): 3350, 2922, 2858, 2224, 1667, 1634, 1445, 1265, 1005, 727; HRMS (ESIꢀTOF)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
calcd for C H ClN O [M+NH ] 285.1728, found 285.1726.
1
5
26
2
4
(
2Z,6E)ꢀ2ꢀ(Chloromethyl)ꢀ9ꢀ((2R,3R)ꢀ3ꢀ(hydroxymethyl)ꢀ2ꢀmethyloxiranꢀ2ꢀyl)ꢀ6ꢀmethylnonaꢀ
,6ꢀdienenitrile (S5). In a 10 mL roundꢀbottom flask, 4 Å molecular sieves (115 mg) was
dispersed in anhydrous CH Cl (5.4 mL). Dꢀ(–)ꢀdiisopropyl tartrate (11 µL, 0.050 mmol) was
2
2
2
o
added to the reaction flask and the mixture was cooled to –40 C. After 10 min, Ti(OꢀiꢀPr) (14
4
o
µL, 0.047 mmol) was added and stirred at –40 C for 15 min. After that time, TBHP (3.3 M in
o
toluene, 0.20 mL, 0.660 mmol) was introduced and the mixture was stirred at –40 C for 30 min,
then a solution of S4 (115 mg, 0.431 mmol) in dry CH Cl (1 mL) was added. The reaction
2
2
o
mixture was warmed to –18 C and kept at this temperature overnight. The reaction was
quenched by addition of acetone containing 2% water (5 mL), warmed to room temperature and
stirred for 3 h. After filtering through Celite, the solvent was dried over MgSO and concentrated
4
under reduced pressure. The crude mixture was purified by column chromatography (0–35%
ethyl acetate/hexane) to provide S5 as a colorless oil (107 mg, 0.378 mmol, 88%, ee = 87%).
2
0
1
[α]D = 12.0 (c = 1.0, CHCl ); H NMR (400 MHz, CDCl ) δ 6.54 (t, J = 7.6 Hz, 1H), 5.14 (t, J
3
3
=
6.7 Hz, 1H), 4.11 (s,2H), 3.83–3.75 (m, 1H), 3.70–3.63 (m, 1H), 2.94 (dd, J = 6.5, 4.4 Hz, 1H),
2
.38 (q, J = 7.4 Hz, 2H), 2.23 (br s, 1H), 2.17–2.03 (m, 4H), 1.60 (s, 3H), 1.68–1.49 (m, 2H),
1
3
1.28 (s, 3H); C NMR (100 MHz, CDCl ) δ 152.6, 133.1, 125.8, 118.2, 112.3, 63.0, 61.5, 61.0,
3
−1
3
8.3, 38.2, 37.7, 27.1, 23.6, 16.8, 15.9; IR (KBr, cm ): 3445, 2927, 2859, 2224, 1634, 1448,
+
1
388, 1263, 1031, 726; HRMS (ESIꢀTOF) calcd for C H ClN O [M+NH ] 301.1677, found
15 26
2
2
4
301.1679.
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(
2Z,6E)ꢀ2ꢀ(Chloromethyl)ꢀ9ꢀ((2R,3S)ꢀ3ꢀformylꢀ2ꢀmethyloxiranꢀ2ꢀyl)ꢀ6ꢀmethylnonaꢀ2,6ꢀ
dienenitrile (22b). To a solution of S5 (71 mg, 0.251 mmol) in CH Cl (3.6 mL) was added
2
2
NaHCO (210 mg, 2.500 mmol) and Dess–Martin periodinane (212 mg, 0.499 mmol) at room
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
temperature. After 1 h, sat. aq. NaHCO (5 mL) was added, and reaction was stirred at room
3
temperature for 10 min. The CH Cl layer was separated. The aqueous layer was extracted with
2
2
CH Cl (2 × 5 mL). The CH Cl layer was combined, dried over Na SO and concentrated under
2
2
2
2
2
4
reduced pressure. The crude product was purified by flash chromatography (0–15% ethyl
2
0
acetate/hexane) to yield 22b (64 mg, 0.228 mmol, 91%) as a clear colorless oil. [α]D = –54.0 (c
1
=
1.0, CHCl ); H NMR (400 MHz, CDCl ) δ 9.45 (d, J = 5.0 Hz, 1H), 6.52 (t, J = 7.6 Hz, 1H),
3
3
5.16–5.10 (m, 1H), 4.14 (s, 2H), 3.16 (d, J = 5.0 Hz, 1H), 2.40 (q, J = 7.5 Hz, 2H), 2.18–2.09 (m,
1
3
4H), 1.77–1.68 (m, 1H), 1.64–1.55 (m, 1H), 1.61 (s, 3H), 1.44 (s, 3H); C NMR (100 MHz,
CDCl ) δ 199.8, 152.3 134.0, 124.8, 118.1, 112.5, 64.0, 63.6, 38.3, 38.1, 37.7, 27.1, 23.5, 17.3,
3
−
1
1
6.0; IR (KBr, cm ): 2923, 2853, 2223, 1721, 1634, 1449, 1405, 1264, 1240, 799; HRMS (ESIꢀ
+
TOF) calcd for C H ClN O [M+NH ] 299.1521, found 299.1523.
1
5
24
2
2
4
2
ꢀ((1S,2S,3R,10R,E)ꢀ2ꢀHydroxyꢀ6,10ꢀdimethylꢀ11ꢀoxabicyclo[8.1.0]undecꢀ6ꢀenꢀ3ꢀ
yl)acrylonitrile (23). Under Ar, to a solution of CrCl (532 mg, 4.329 mmol) in dry DMF (60 mL)
2
was added a solution of 22a (120 mg, 0.427 mmol) in 10 mL dry DMF over 2 h at room
temperature. The reaction mixture was allowed to stir for another 8 h and quenched with 30 mL
of water. The reaction mixture was extracted with Et O. The combined extracts were washed
2
with water, then brine, dried over MgSO and filtered. After removal of the solvent under
4
reduced pressure, the crude product was purified by flash chromatography (0–20% ethyl
acetate/hexane) to provide 23 as a colorless oil (38 mg, 0.154 mmol, 36%); Under Ar, to a
stirring solution of CrCl (123 mg, 1.001 mmol) in dry DMF (16 mL) was added a solution of the
2
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
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4
4
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5
5
5
5
5
5
5
5
5
6
2
2b (33 mg, 0.117 mmol) in 2 mL dry DMF over 2 h at room temperature. The reaction mixture
was allowed to stir for another 4 h at the same temperature and quenched with 8 mL of water.
The reaction mixture was extracted with Et O. The combined extracts were washed with water
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
and brine, dried over MgSO , and filtered. After removal of the solvent under reduced pressure,
4
the crude residue was purified by flash chromatography (0–20% ethyl acetate/hexane) to give 23
2
0
1
(11.4 mg, 0.046 mmol, 39%). [α]D = –77.2 (c = 1.0, CHCl ); H NMR (400 MHz, CDCl ) δ
3
3
5
.97 (s, 1H), 5.89 (d, J = 1.1 Hz, 1H), 5.36–5.24 (m, 1H), 3.64 (d, J = 7.7 Hz, 1H), 2.62 (br s,
1H), 2.43–2.20 (m, 4H), 2.19–2.00 (m, 3H), 1.90–1.73 (m, 2H), 1.68 (s, 3H), 1.34–1.26 (m, 1H),
1
3
−1
1
.25 (s, 3H); C NMR (100 Hz, CDCl ) δ 130.5, 119.1, 73.4, 67.7, 60.7, 16.5; IR (KBr, cm ):
3
3452, 3107, 2925, 2222, 1884, 1714, 1445, 869; HRMS (ESIꢀTOF) calcd for C H N O
2
1
5
25
2
+
[M+NH ] 265.1911, found 265.1912.
4
2ꢀ((1S,2S,3R,10R,E)ꢀ2ꢀHydroxyꢀ6,10ꢀdimethylꢀ11ꢀoxabicyclo[8.1.0]undecꢀ6ꢀenꢀ3ꢀ
yl)acrylamide (24). Nitrile 23 (188 mg, 0.761 mmol) was dissolved in a DMSO/THF mixture
(2:1, 2.3 mL) containing K CO (33 mg, 0.253 mmol). A solution of 30% aqueous H O (0.94
2
3
2
2
o
o
mL, 8.067 mmol) was added dropwise at 0 C. The reaction mixture was stirred at 30 C for 1.5 h,
then quenched by the addition of brine and extracted several times with Et O. The organic
2
extracts were dried over MgSO , filtered and the solvent was evaporated. The crude product was
4
purified by chromatography on silica gel (50–100% ethyl acetate/hexane) to give product 24 (178
o
20
1
mg, 0.672 mmol, 88%) as a white solid. mp 160–162 C; [α]D = –88.0 (c = 1.0, CHCl ); H
3
NMR (400 MHz, CDCl ) δ 6.73 (s, 1H), 6.31 (s, 1H), 5.68 (s, 1H), 5.38 (s, 1H), 5.35–5.20 (m,
3
1
H), 3.46 (d, J = 7.7 Hz, 1H), 2.68–2.45 (m, 2H), 2.43–2.27 (m, 1H), 2.25–1.92 (m, 4H), 1.85–
1
3
1
.70 (m, 1H), 1.64 (s, 3H), 1.56–1.45 (m, 1H), 1.33–1.20 (m, 1H), 1.25 (s, 3H); C NMR (100
MHz, CDCl ) δ 172.5, 148.5, 137.2, 123.7, 120.8, 74.9, 68.2, 60.1, 46.3, 37.3, 24.8, 23.1, 16.6;
3
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–1
IR (KBr, cm ): 3372, 3187, 2480, 1668, 1437, 826; HRMS (ESIꢀTOF) calcd for C H NO
3
1
5
24
+
[
M+H ] 266.1751, found 266.1749.
7
ꢀepiꢀParthenolide (19). Compound 24 (38.0 mg, 0.143 mmol) and DBU (43.6 mg, 0.287
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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38
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
mmol) was dissolved in 8.3 mL of benzene. The reaction mixture was refluxed for 12 h and
concentrated under vacuum. The residue was submitted to silica gel chromatography (0–10%
ethyl acetate/hexane) to provide 19 as a white solid (33.1 mg, 0.133 mmol, 93%).
tertꢀButyldiphenyl(((2E,6Z)ꢀ3,7,11ꢀtrimethyldodecaꢀ2,6,10ꢀtrienꢀ1ꢀyl)oxy)silane
(S6).
TBDPSCl (17.3 mL, 66.249 mmol) was added to a solution of 25 (13.0 g, 58.463 mmol) and
o
imidazole (4.9 g, 71.974 mmol) in anhydrous dichloromethane (130 mL) at 0 C. The reaction
mixture was stirred for 1 h, and then it was diluted with dichloromethane, poured over water, and
extracted with more dichloromethane. The combination of organic layer was dried over
magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The crude
product was purified by column chromatography (0–2% ethyl acetate/hexane ) to afford S6 as a
1
colorless oil (26.9 g, 58.478 mmol, 99%). H NMR (400 MHz, CDCl ) δ 7.74–7.70 (m, 4H),
3
7.48–7.36 (m, 6H), 5.42 (t, J = 5.8 Hz, 1H), 5.19–5.12 (m, 2H), 4.26 (d, J = 6.3 Hz, 2H), 2.14–
1
3
2
.04 (m, 6H), 2.03–1.97 (m, 2H), 1.72 (s, 6H), 1.64 (s, 3H), 1.47 (s, 3H), 1.08 (s, 9H); C NMR
(100 MHz, CDCl ) δ 137.2, 135.8, 135.5, 134.3, 131.7, 129.7, 127.8, 125.0, 124.6, 124.3, 61.4,
3
–1
4
1
4
0.0, 32.2, 27.0, 26.8, 26.4, 25.9, 23.6, 19.4, 17.8, 16.5; IR (KBr, cm ): 3070, 3048, 2929, 2858,
+
666, 1587, 1427, 1108, 1059, 702; HRMS (ESIꢀTOF) calcd for C H NOSi [M+NH ]
31 48
4
78.3500, found 478.3493.
tertꢀButyl(((2E,6Z)ꢀ9ꢀ(3,3ꢀdimethyloxiranꢀ2ꢀyl)ꢀ3,7ꢀdimethylnonaꢀ2,6ꢀdienꢀ1ꢀ
yl)oxy)diphenylsilane (S7). To a solution of S6 (3.26 g, 7.087 mmol) in 76 mL THF/H O = 3/1 (6
2
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mL) was added Nꢀbromosuccinimide (1.4 g, 7.865 mmol) in small portions over a period of 1 h
o
at 0 C. After 1 h, 250 mL of ether were added and the organic layer was washed with brine. The
organic layer was dried over anhydrous MgSO , and then concentrated under reduced pressure to
4
0
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2
3
4
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9
0
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8
9
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9
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9
0
afford the crude bromohydrin. The crude bromohydrin was dissolved in a slurry of K CO (1.75 g,
2
3
12.655 mmol) in methanol (30 mL). After 1 h, most of the methanol was removed under reduced
pressure and the residue was extracted with diethyl ether to afford crude product. The crude
product was purified by flash silica gel chromatography (0–1% ethyl acetate/hexane ) to yield the
1
S7 (2.26 g, 4.748 mmol, 67%) as a colorless oil. H NMR (400 MHz, CDCl ) δ 7.75–7.65(m,
3
4
H), 7.47–7.32 (m, 6H), 5.39 (t, J = 6.3Hz, 1H), 5.17 (t, J = 6.6 Hz, 1H), 4.23 (d, J = 6.2 Hz, 2H),
.72 (t, J = 6.4 Hz, 1H), 2.22–2.14 (m, 2H), 2.13–2.05 (m, 2H), 2.03–1.95 (m, 2H), 1.71 (d, J =
2
1
3
1.0 Hz, 3H), 1.68–1.53 (m, 2H), 1.45 (s, 3H), 1.31 (s, 3H), 1.28 (s, 3H), 1.05 (s, 9H); C NMR
(
100 MHz, CDCl ) δ 137.0, 135.8, 134.5, 134.3 129.7, 127.7, 125.6, 124.4, 64.3, 61.3, 58.5, 39.8,
3
ꢀ1
2
8.7, 27.6, 27.0, 26.3, 25.1, 23.5, 19.4, 18.9, 16.5; IR (KBr, cm ): 2931, 2859, 1462, 1427, 1109,
+
1058, 703; HRMS (ESIꢀTOF) calcd for C H NO Si [M+NH ] 494.3449, found 494.3452.
3
1
48
2
4
(4Z,8E)ꢀ10ꢀ((tertꢀButyldiphenylsilyl)oxy)ꢀ4,8ꢀdimethyldecaꢀ4,8ꢀdienal (26). A solution of S7
(
2.51 g, 5.273 mmol, 1 eq.) in THF:H O (82:18, 39 mL) was treated with NaIO (641 mg, 2.997
2
4
o
mmol, 0.6 equiv) and HIO •2H O (1.32 g, 5.792 mmol, 1.1 equiv) at 0 C. The mixture was
4
2
o
stirred at 0 C for 10 min and then warmed to room temperature. After 1 h, the reaction mixture
were quenched with saturated aqueous NaHCO (25 mL), and aqueous layer was extracted with
3
EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over Na SO ,
2
4
and concentrated in vacuum. The crude product was purified by silica gel chromatography (0–1%
ethyl acetate/hexane) to give the desired aldehyde 26 (2.21 g, 5.092 mmol, 96%) as a colorless
1
oil. H NMR (400 MHz, CDCl ) δ 9.78 (t, J = 1.7 Hz, 1H), 7.72–7.66 (m, 4H), 7.45–7.35 (m,
3
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H), 5.38 (t, J = 6.4 Hz, 1H), 5.18 (t, J = 6.7 Hz, 1H), 4.23 (d, J = 6.2 Hz, 2H), 2.53–2.44 (m,
2
H), 2.35 (t, J = 7.6 Hz, 2H), 2.13–2.05 (m, 2H), 1.99 (t, J = 6.8 Hz, 2H), 1.69 (s, 3H), 1.45 (s,
1
3
3
H), 1.06 (s, 9H); C NMR (101 MHz, CDCl ) δ 202.4, 136.8, 135.8, 134.3, 133.2, 129.7, 127.8,
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
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54
55
56
57
58
59
60
ꢀ1
1
26.4, 124.5, 61.3, 42.5, 39.7, 27.0, 26.2, 24.5, 23.2, 19.4, 16.5; IR (KBr, cm ): 3070, 2857,
+
2
717, 1725, 1384, 1108, 703; HRMS (ESIꢀTOF) calcd for C H NO Si [M+NH ] 452.2979,
28 42
2
4
found 452.2976.
(
6Z,10E)ꢀ12ꢀ((tertꢀButyldiphenylsilyl)oxy)ꢀ3ꢀhydroxyꢀ6,10ꢀdimethylꢀ2ꢀmethylenedodecaꢀ6,10ꢀ
dienenitrile (S8). A solution of aldehyde 26 (1.89 g, 4.354 mmol) and DABCO (97 mg, 0.866
mmol) in acrylonitrile (8.6 mL, 131.285 mmol) was stirred at room temperature for 2 days, then
additional DABCO (97 mg, 0.866 mmol) was added and the mixture was stirred at room
temperature for another 20 days. The mixture was concentrated and the residue was purified by
silica gel chromatography (0–10% ethyl acetate/hexane) to give the S8 (1.73 g, 3.550 mmol,
1
8
2 %) as a colorless oil. H NMR (400 MHz, CDCl ) δ 7.72–7.66 (m, 4H), 7.46–7.34 (m, 6H),
3
6.00 (s, 1H), 5.97 (s, 1H), 5.38 (t, J = 5.6 Hz, 1H), 5.19 (t, J = 6.8 Hz, 1H), 4.26–4.17 (m, 3H),
2
.21–2.05 (m, 4H), 2.03–1.96 (m, 3H), 1.90–1.80 (m, 1H), 1.71 (d, J = 0.9 Hz, 3H), 1.45 (s, 3H),
1
3
1
.05 (s, 9H); C NMR (100 MHz, CDCl ) δ 136.9, 135.8, 134.3, 134.0, 129.9, 129.7, 127.8,
3
ꢀ
127.1, 126.5, 124.5, 117.1, 72.3, 61.3, 39.7, 33.9, 27.6, 27.1, 26.3, 23.3, 19.4, 16.6; IR (KBr, cm
1
)
: 3478, 2926, 2856, 2227, 1432, 1108, 704; HRMS (ESIꢀTOF) calcd for C H N O Si
31 45 2 2
+
[
M+NH ] 505.3245, found 505.3238.
4
(2E,6Z,10E)ꢀ12ꢀ((tertꢀButyldiphenylsilyl)oxy)ꢀ2ꢀ(chloromethyl)ꢀ6,10ꢀdimethyldodecaꢀ2,6,10ꢀ
trienenitrile (27a) and (2Z,6Z,10E)ꢀ12ꢀ((tertꢀbutyldiphenylsilyl)oxy)ꢀ2ꢀ(chloromethyl)ꢀ6,10ꢀ
dimethyldodecaꢀ2,6,10ꢀtrienenitrile (27b). To a solution of S8 (427 mg, 0.877 mmol ) in dry
CCl (9 mL) was added nꢀBu P (0.32 mL, 1.30 mmol) at room temperature under Ar. The
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3
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reaction mixture was stirred for 2 h, concentrated under reduced pressure. The crude residue was
purified by column chromatography (0–1% ethyl acetate/hexane) to afford 27a (296 mg, 0.586
mmol, 67%) and 27b (99 mg, 0.196 mmol, 22%).
0
1
2
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0
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8
9
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0
1
2
7a: H NMR (400 MHz, CDCl ) δ 7.74–7.64 (m, 4H), 7.46–7.35 (m, 6H), 6.48 (t, J = 7.7 Hz,
3
1H), 5.38 (t, J = 5.8 Hz, 1H), 5.21 (t, J = 6.7 Hz, 1H), 4.23 (d, J = 6.2 Hz, 2H), 4.09 (s, 2H), 2.52
(q, J = 7.5 Hz, 2H), 2.21 (t, J = 7.4 Hz, 2H), 2.10–2.03 (m, 2H), 2.02–1.95 (m, 2H), 1.71 (s, 3H),
1
3
1
.45 (s, 3H), 1.05 (s, 9H); C NMR (100 MHz, CDCl ) δ 151.5, 136.8, 135.8, 134.3, 132.8,
3
129.7, 127.8, 127.0, 124.6, 115.5, 112.6, 61.3, 44.0, 39.7, 30.3,29.9, 27.0, 26.4, 23.3, 19.4, 16.5;
−
1
IR (KBr, cm ): 3070, 3046, 2932, 2858, 2223, 1589, 1427, 1108, 1058, 705; HRMS (ESIꢀTOF)
+
calcd for C H ClN OSi [M+NH ] 523.2906, found 523.2900.
3
1
44
2
4
1
27b: H NMR (400 MHz, CDCl ) δ 7.73–7.66 (m, 4H), 7.48–7.31 (m, 6H), 6.54 (t, J = 7.7 Hz,
3
1H), 5.43–5.33 (m, 1H), 5.23 (t, J = 6.5 Hz, 1H), 4.23 (d, J = 6.2 Hz, 2H), 4.11 (s, 2H), 2.38 (q, J
=
7.6 Hz, 2H), 2.19 (t, J = 7.5 Hz, 2H), 2.09–2.04 (m, 2H), 2.03–1.95 (m, 2H), 1.69 (d, J= 1.0 Hz,
1
3
3H), 1.45 (s, 3H), 1.05 (s,9H); C NMR (100 MHz, CDCl ) δ 152.3, 136.6, 135.8, 134.3, 132.6,
3
129.7, 127.8, 127.3, 124.7, 118.1, 112.6, 61.3, 39.7, 38.2, 30.3, 27.3, 27.0, 26.4, 23.2, 19.4, 16.5;
−
1
IR (KBr, cm ): 3070, 3046, 2931, 2858, 2223, 1591, 1427, 1108, 1058, 704; HRMS (ESIꢀTOF)
+
calcd for C H ClN OSi [M+NH ] 523.2906, found 523.2896.
3
1
44
2
4
(
2E,6Z,10E)ꢀ2ꢀ(Chloromethyl)ꢀ12ꢀhydroxyꢀ6,10ꢀdimethyldodecaꢀ2,6,10ꢀtrienenitrile (S9). To a
solution of 27a (140 mg, 0.277mmol) in THF (4.2 mL) was added pyridine hydrofluoride (70%,
.24 mL, 1.714 mmol). The reaction mixture was stirred for 2.5 h, and then diluted with
0
dichloromethane (40 mL). The resulting solution was then washed with saturated aqueous
sodium bicarbonate solution (10 mL), and then the organic phase was dried over magnesium
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sulfate and the solvent was removed under reduced pressure. The crude product was purified by
column chromatography (0–30% ethyl acetate/hexane) to afford S9 (59 mg, 91%) as a colorless
1
oil. H NMR (400 MHz, CDCl ) δ 6.49 (t, J = 7.7 Hz, 1H), 5.41 (t, J = 6.3 Hz, 1H), 5.20 (t, J =
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6
.5 Hz, 1H), 4.15 (d, J = 6.8 Hz, 2H), 4.10 (s, 2H), 2.51 (q, J = 7.5 Hz, 2H), 2.19 (t, J = 7.5 Hz,
1
3
2
H), 2.14–1.98 (m, 4H), 1.71 (d, J= 0.7 Hz, 3H), 1.67 (s, 3H), 1.30 (br s, 1H); C NMR (100
MHz, CDCl ) δ 151.5, 139.3, 133.0, 126.8, 123.8, 115.6, 112.7, 59.5, 44.0, 39.7, 30.4, 30.0, 26.4,
3
ꢀ1
23.3, 16.5; IR (KBr, cm ): 3345, 2925, 2864, 2224, 1636, 1444, 1000, 715; HRMS (ESIꢀTOF)
+
calcd for C H ClN O [M+NH ] 285.1728, found 285.1730.
1
5
26
2
4
(
2E,6Z)ꢀ2ꢀ(Chloromethyl)ꢀ9ꢀ((2R,3R)ꢀ3ꢀ(hydroxymethyl)ꢀ2ꢀmethyloxiranꢀ2ꢀyl)ꢀ6ꢀmethylnonaꢀ
,6ꢀdienenitrile (S10). In a 10 mL roundꢀbottom flask, 4 Å molecular sieves (250 mg) were
dispersed in anhydrous CH Cl (8.6 mL). Dꢀ(–)ꢀdiisopropyl tartrate (24 µL, 0.112 mmol) was
2
2
2
o
added to the reaction flask and the mixture was cooled to –40 C. After 10 min, Ti(OꢀiꢀPr) (28
4
o
µL, 0.093 mmol) was added and stirred at –40 C for 15 min. After that time, TBHP (3.3 M in
o
toluene, 0.42 mL,1.386 mmol) was introduced and the mixture was stirred at –40 C for 30 min,
then S9 (250 mg, 0.936 mmol) in dry CH Cl (3 mL) was added. The reaction mixture was
2
2
o
warmed to –18 C and kept at this temperature overnight. The reaction was quenched by addition
of acetone containing 2% water (9 mL), warmed to room temperature and stirred for 3 h. After
filtering through Celite, the solvent was dried over MgSO , concentrated under reduced pressure.
4
The crude mixture was purified by column chromatography (0–35% ethyl acetate/hexane) to
2
0
provide compound S10 as a colorless oil (246 mg, 0.871 mmol, 93%, ee = 97%). [α]D = 1.6 (c
1
=
1.0, CHCl ); H NMR (400 MHz, CDCl ) δ 6.50 (t, J = 7.8 Hz, 1H), 5.18 (t, J = 7.0 Hz, 1H),
3
3
4.10 (s, 2H), 3.83–3.74 (m, 1H), 3.72–3.62 (m, 1H), 2.96 (dd, J = 6.4, 4.6 Hz, 1H), 2.49 (q, 7.6
Hz, 2H), 2.19 (t, J= 7.5 Hz, 2H), 2.13–2.02 (m, 3H), 1.70 (d, J = 0.9 Hz, 3H), 1.63 (dt, J = 13.5,
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
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5
5
5
5
6
13
7
.6 Hz, 1H), 1.51 (ddd, J = 21.1, 10.6, 5.9 Hz, 1H), 1.28 (s, 3H); C NMR (100 MHz, CDCl ) δ
3
1
51.4, 133.4, 126.2, 115.6, 112.8, 62.9, 61.5, 61.1, 44.0, 38.6, 30.3, 29.9, 23.6, 23.3, 17.0; IR
ꢀ1
(
KBr, cm ): 3434, 2933, 2224, 1447, 1207, 1031, 714; HRMS (ESIꢀTOF) calcd for
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
C H ClNO [M+H ] 284.1412, found 284.1412.
1
5
23
2
(
2E,6Z)ꢀ2ꢀ(Chloromethyl)ꢀ9ꢀ((2R,3S)ꢀ3ꢀformylꢀ2ꢀmethyloxiranꢀ2ꢀyl)ꢀ6ꢀmethylnonaꢀ2,6ꢀ
dienenitrile (28a). To a solution of S10 (195 mg, 0.689 mmol) in CH Cl (10 mL) was added
2
2
NaHCO (579 mg, 6,893 mmol) and Dess–Martin periodinane (585 mg, 1,379 mmol) at room
3
temperature. After 1 h, sat. aq. NaHCO (10 mL) were added and the reaction was stirred at room
3
temperature for 10 min. The CH Cl layer was separated and the aqueous layer was extracted
2
2
with CH Cl (2 × 10 mL). The CH Cl layers were combined, dried over anhydrous Na SO and
2
2
2
2
2
4
concentrated under reduced pressure. The crude residue was purified by flash chromatography
(
0–15% ethyl acetate/hexane) to afford 28a (186 mg, 0.662 mmol, 96%) as a clear colorless oil.
2
0
1
[
α]D = –52.8 (c = 1.0, CHCl ); H NMR (400 MHz, CDCl ) δ 9.46 (d, J = 4.9 Hz, 1H), 6.49 (t,
3
3
J = 7.7 Hz, 1H), 5.17 (t, J = 7.1 Hz, 1H), 4.10 (s, 2H), 3.19 (d, J = 4.9 Hz, 1H), 2.50 (q, J = 7.6
Hz, 2H), 2.19 (t, J = 7.5 Hz, 2H), 2.13–2.04 (m, 2H), 1.72 (d, J = 1.0 Hz, 3H), 1.69–1.58 (m, 2H),
1
3
1
.43 (s, 3H); C NMR (100 MHz, CDCl ) δ 199.6, 151.1, 134.1, 125.5, 115.5, 112.9, 64.1, 63.6,
3
−
1
44.0, 38.3, 30.3, 29.9, 23.34, 23.27, 17.4; IR (KBr, cm ): 2962, 2936, 2860, 2223, 1720, 1447,
+
1
270, 714; HRMS (ESIꢀTOF) calcd for C H ClNO [M+H ] 282.1255, found 282.1254.
1
5
21
2
(
2Z,6Z,10E)ꢀ2ꢀ(Chloromethyl)ꢀ12ꢀhydroxyꢀ6,10ꢀdimethyldodecaꢀ2,6,10ꢀtrienenitrile (S11). To
a solution of 27b (110 mg, 0.218 mmol) in THF (3.3 mL) was added pyridine hydrofluoride
70%, 0.19 mL, 1.357 mmol). The reaction mixture was stirred for 2.5 h, and then diluted with
(
dichloromethane (30 mL). The resulting solution was then washed with saturated aqueous
sodium bicarbonate solution (10 mL), and then the organic phase was dried over magnesium
28
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Page 29 of 58
Journal of Medicinal Chemistry
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sulfate and the solvent was removed under reduced pressure and purified by column
chromatography (0–30% ethyl acetate/hexane) to afford S11 (52 mg, 0.196 mmol, 90%) as a
1
colorless oil. H NMR (400 MHz, CDCl ) δ 6.54 (t, J = 7.8 Hz, 1H), 5.41 (td, J = 6.9, 1.1 Hz,
3
10
11
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H), 5.22 (t, J = 6.6 Hz, 1H), 4.16 (d, J = 6.8 Hz, 2H), 4.13 (s, 2H), 2.38 (q, J = 7.5 Hz, 2H), 2.20
1
3
(t, J = 7.4 Hz, 2H), 2.15–2.00 (m, 4H), 1.69 (d, J = 1.0 Hz, 3H), 1.68 (s, 3H), 1.25 (br s, 1H); C
NMR (100 MHz, CDCl ) δ 152.3, 139.2, 132.7, 127.1, 123.9, 118.1, 112.6, 59.5, 39.7, 38.2, 30.2,
3
ꢀ1
27.2, 26.4, 23.2, 16.5; IR (KBr, cm ): 3345, 2958, 2735, 2224, 1634, 1446; HRMS (ESIꢀTOF)
+
calcd for C H ClN O [M+NH ] 285.1728, found 285.1733.
1
5
26
2
4
(
2Z,6Z)ꢀ2ꢀ(Chloromethyl)ꢀ9ꢀ((2R,3R)ꢀ3ꢀ(hydroxymethyl)ꢀ2ꢀmethyloxiranꢀ2ꢀyl)ꢀ6ꢀmethylnonaꢀ
,6ꢀdienenitrile (S12). In a 10 mL roundꢀbottom flask, 4 Å molecular sieves (80 mg) were
dispersed in anhydrous CH Cl (2.5 mL). Dꢀ(–)ꢀdiisopropyl tartrate (7.7 µL, 0.036 mmol) was
2
2
2
o
added to the reaction flask and the mixture was cooled to –40 C. After 10 min, Ti(OꢀiꢀPr) (0.90
4
o
µL, 0.030 mmol) was added and stirred at –40 C for 15 min. After that time, TBHP (3.3 M in
o
toluene, 0.13 mL,0.429 mmol) was introduced and the mixture was stirred at –40 C for 30 min,
then S11 obtained above (79 mg, 0.296 mmol) was added as a solution in dry CH Cl (1 mL).
2
2
o
The reaction mixture was warmed to –18 C and kept at this temperature overnight. The reaction
was quenched by addition of acetone containing 2% water (3 mL), warmed to room temperature
and stirred for 3 h. After filtering through Celite, the solvent was dried over MgSO4,
concentrated under reduced pressure. The crude mixture was purified by column chromatography
(0–35% ethyl acetate/hexane) to provide compound S12 as a colorless oil (76 mg, 0.269 mmol,
20
1
9
1
6
1%, ee = 95%). [α]D = 6.6 (c = 1.0, CHCl ); H NMR (400 MHz, CDCl ) δ 6.54 (t, J = 7.8 Hz,
3
3
H), 5.21 (t, J = 7.1 Hz, 1H), 4.13 (s, 2H), 3.86–3.78 (m, 1H), 3.74–3.64 (m, 1H), 2.97 (dd, J =
.5, 4.4 Hz, 1H), 2.38 (q, J = 7.5 Hz, 2H), 2.23–1.16 (m, 2H), 2.07 (q, J = 7.5 Hz, 2H), 1.87 (br s,
29
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